In this program project application, we present three proposals designed to study clonogenic cell systems from two perspectives and to combine these studies with a unique approach to drug development which emphasizes the relationship of the carrier to the drug. The drug development scheme is to be tested in the clonogenic cell assay systems. Cell culture techniques available in Dr. Smith and Dr. Sikic's laboratories will be examined for their potential use in drug development. This will be accomplished by studying the response of these systems to a variety of adriamycin derivatives that have been thoroughly studied in other systems and to compare results between the two culture systems and the previous in vivo and in vitro characterizations. While these studies are proceeding, work will be initiated by Drs. Papahadjopoulos and Acton on the examination of the interaction of adriamycin with liposomes. The basic concept of these experiments is to adapt the drug to the requirements of its carrier as well as its culture systems and compared with the in vivo studies. Thus, an initial test of the systems in a real chemotherapy development situation will be available. There are four laboratory units involved in the three proposals. The first unit is that of Dr. Demetrios Papahadjopoulos. His expertise is in synthetic lipid vesicles (liposomes). One of his major interests is in the use of liposomes as carriers of drugs used in cancer chemotherapy. The second unit is that of Dr. Branimir Sikic. His major interest is in cancer pharmacology. Recently, he has studied possible applications of the human tumor clonogenic assays to the cellular pharmacology of anticancer agents as well as possible clinical applications. The third unit is Dr. Helene Smith and her colleagues. They have recently made exciting advances in the culture of human breast cells from both normal and tumor tissue. The fourth unit is that of Dr. Edward Acton of SRI, International. Dr. Acton is a synthetic organic chemist who has been responsible for the synthesis of numerous derivatives of the drug adriamycin.